ABSTRACT Mental and neurological disorders such as frontotemporal dementia and drug addiction can be characterized as patients making ?poor choices.? Specifically affected are choices based on subjective preferences, also referred to as economic choices. Thus to better understand the origins of these disorders and to pave the way for treatments, it is critical to understand the neural underpinnings of this behavior. Economic choices are thought to involve two mental stages ? values are assigned to the available options and a decision is made by comparing values. Evidence from clinical data, lesion studies, functional imaging and neurophysiology links economic decisions to the orbitofrontal cortex (OFC). In particular, work in my lab examined the activity of OFC neurons in monkeys choosing between different juices. We thus identified three populations intimately related to the decision: offer value cells encoding the value of individual juices; chosen value cells encoding the value of the chosen juice; and chosen juice cells encoding the identity of the chosen juice independent of quantity. Notably, these groups of cells capture both the input (offer value) and the output (chosen juice, chosen value) of the decision process, suggesting that decisions might be generated within OFC. The overarching goal of this proposal is to shed light onto the organization and mechanisms of this neural circuit. Using a combination of behavioral, computational and neurophysiology techniques, we will pursue two Specific Aims. Aim 1 focuses on choices under sequential offers. The vast majority of previous studies examined choices between goods offered simultaneously. Exp.1 will establish whether current notions generalize to choices under sequential offers, which are arguably more relevant to real-life decisions. Furthermore, by dissociating value computation from value comparison, Exp.1 will address outstanding questions on the decision circuit. Aim 2 focuses on the fundamental question of causality. Despite the enormous advances of recent years, our understanding of the mechanisms underlying economic decisions remains tentative. This is primarily because causal links between OFC activity and decisions have not yet been established. In principle, such links may be demonstrated using electrical stimulation to bias choices in a predictable way, but the absence of columnar organization in OFC makes this approach more difficult. To obviate this issue, we designed three experimental protocols. In Exp.2, monkeys will perform choices under sequential offers. By injecting current during one of the offers, we will bias the animal's decision. Exp.3 and Exp.4 will focus on specific groups of cells. The experiments will take advantage of phenomena recently discovered in my lab, namely the range adaptation of offer value cells (Exp.3), the predictive activity of chosen juice cells and choice hysteresis (Exp.4). The first cycle of this grant has generated multiple breakthroughs, and the current Specific Aims build on our previous results. By fulfilling them, the research described here will significantly advance our understanding of the neural mechanisms that underlie economic decisions and that malfunction in mental illness.